Non-squamous Carcinoma Research Articles

Concordance of programmed death-ligand 1 expression between primary and metastatic non-small cell lung cancer by immunohistochemistry and RNA in situ hybridization.

We investigated the concordance of programmed death-ligand 1 (PD-L1) expression between primary cancer at initial diagnosis and metastasis at recurrence in resected non-small cell lung cancer (NSCLC). PD-L1 expression was evaluated using the SP142 assay in 37 NSCLC patients with paired primary lung cancer and surgically resected metastases at recurrence. PD-L1 positivity was defined as immunohistochemistry (IHC) and also evaluated by RNA in situ hybridization (RISH). The concordance rate of PD-L1 between primaries and metastases and correlation with clinicopathological factors were analyzed. PD-L1 expression was higher in squamous cell carcinoma, wild-type EGFR, and smokers than in non-squamous carcinoma, mutant EGFR, and never smokers, respectively. PD-L1 positivity was observed in 18.9% of primaries and 21.6% of metastases. IHC demonstrated 78.4% concordance of PD-L1 positivity between primary and metastatic cancers. In 10.8% of cases, PD-L1 positivity was higher in primaries than in metastases, and vice versa in the remaining 10.8%. By PD-L1 RISH, 35.1% of primaries and 27.0% of metastases demonstrated PD-L1 positivity. There was 62.2% concordance in PD-L1 by RISH between the primaries and metastases. Our results thus highlight the clinical importance of replacing metastases with primary archival tissue, particularly when re-biopsy is difficult at recurrence.

Selection of Non-small Cell Lung Cancer Patients for Intercalated Chemotherapy and Tyrosine Kinase Inhibitors.

BackgroundWhen treating patients with advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors and chemotherapy, intercalated schedule with time separation between the two classes of drugs should avoid their mutual antagonism. In a survey of published trials, we focus on relation between eligibility criteria and effectiveness of intercalated treatment.MethodsPublished documents were identified using major medical databases, conference proceedings and references of published trials. Median progression-free survival (PFS) was taken as the basic parameter of treatment efficacy. Correlation between characteristics of patients and median PFS was assessed through the Pearson’s correlation coefficient and the coefficient of determination, separately for first-line and second-line setting.ResultsThe series includes 11 single-arm trials and 18 randomized phase II or phase III trials with a total of 2903 patients. Treatment-naive patients or those in progression after first-line treatment were included in 16 and 13 trials, respectively. In 14 trials, only patients with non-squamous histology were eligible. Proportion of patients with non-squamous carcinoma (in first-line setting), proportion of never-smokers (both in first- and second-line setting) and proportion of epidermal growth factor receptor (EGFR) mutant patients (both in first- and second-line setting) showed a moderate or strong correlation with median PFS. In six trials of intercalated treatment applied to treatment-naive EGFR-mutant patients, objective response was confirmed in 83.1% of cases and median PFS was 18.6 months.ConclusionsMost suitable candidates for intercalated treatment are treatment-naive patients with EGFR-mutant tumors, as determined from biopsy or liquid biopsy. For these patients, experience with intercalated treatment is most promising and randomized trials with comparison to the best standard treatment are warranted.

Abstract 3989: Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer

Abstract Although checkpoint inhibitors targeting PD-1/PD-L1 pathway have demonstrated similar clinical activity in treatment of NSCLC both for squamous(SCC) and non-squamous carcinoma (non-SCC) patients, the predictive role of PD-L1 expression is distinct between two histologies in clinical trials. In order to investigated the expression and prognostic roles of PD-1/PD-L1, data from TCGA and GEO database were analyzed and further validated with our original data by IHC in 133 resected NSCLC tumor tissue(49 SCC and 84 non-SCC). Through the analysis of online data, we concluded that PD-L1 expression in SCC was significantly higher than that of non-SCC. In addition, in non-SCC, PD-L1 was associated with immune response and indicated worse prognosis while no such results were observed in SCC. Further, our original data demonstrated PD-L1 expression in tumor cells(TC) and immune cells(IC) were significantly more often and more intense in SCC(P<0.001). In survival analysis, PD-L1 expression in TC and IC were associated with shorter overall survival in non-SCC (P=0.019 and 0.003, respectively). However, in SCC, PD-L1 did not demonstrate any significant effect neither in TC or IC (P=0.526 and 0.674, respectively) which consistent with online data. Contrary to PD-L1, no significant differences of PD-1 expression in tumor infiltrating lymphocytes(TILs) were showed between two histologies. PD-1 in TILs of SCC correlated with worse prognosis (P=0.025) while in non-SCC there was no correlation(P=0.986). Taken together, these findings suggest distinct regulation mechanisms and clinical significance of PD-L1/PD-1 pathway in NSCLC subgroups. Citation Format: Yunpeng Liu, Shuo Wang, Xiujuan Qu, Zhi Liu, Xiaofang Che, Xu Ling, Kezuo Hou, Yibo Fan, Na Song, Ti Wen, Ce Li. Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2017-3989

Abstract 3091: Response of C4.4A-positive patient-derived xenograft models of ESCC, HNSCC and bladder cancer to BAY1129980, a C4.4A-targeted antibody drug conjugate

Abstract C4.4A (LYPD3) is a cancer- and metastasis-associated transmembrane cell surface protein which is expressed at high frequency and density in multiple tumor types including squamous and non-squamous non-small cell lung carcinoma ((NSCLC), head & neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC) and bladder cancer. C4.4A expression is restricted to a limited number of tissues (e.g. suprabasal layer of skin) making C4.4A an attractive target for the treatment of cancer with a C4.4A-targeted antibody-drug conjugate (ADC). BAY 1129980 (C4.4A-ADC), is an ADC consisting of a fully human C4.4A-targeting monoclonal antibody (technology licensed from BioInvent) conjugated via a novel, non-cleavable alkyl hydrazide linker to a novel, highly potent auristatin W, an antimitotic agent (technology licensed from Seattle Genetics, Inc.). This C4.4A-ADC has been previously shown to be efficacious in C4.4A positive cell line-derived and PDX models of NSCLC. Here we present new preclinical efficacy data of C4.4A-ADC in patient-derived xenograft (PDX) models of ESCC, HNSCC and bladder cancer. Models were selected based on tumor C4.4A levels as determined by mRNA levels and immunohistochemistry (IHC), the latter of which allowed ranking of models according to H-score, percentage of C4.4A positivity, and staining intensity (0 to 3+) in the cell membrane. Representative C4.4A-positive models were selected for in vivo efficacy studies (n=7 each): 4 HNSCC, 4 ESCC and 2 bladder cancers. C4.4A-ADC was administered as one cycle (Q4Dx3) at doses of 7.5 and 15 mg/kg, and efficacy was assessed up to 4 weeks post treatment for optimum tumor growth inhibition (TGI). In ESCC models a response to C4.4A ADC was seen in ES0190 (TGI of 77%; 15mg/kg) and in ES0195 (59%). In HNSCC models an ADC effect on tumor growth was observed in HN10847 (46%), HN9619 (34%), and HN10321 (22%). Finally, both bladder models tested were sensitive to treatment, with a transient response seen in BL0597 (41%) and a strong and complete tumor growth control in BL5001 (93%,) which was superior to cisplatin. The data show that C4.4A-positive PDX models of ESCC, HNSCC and bladder cancer can respond to C4.4A-ADC. C4.4A expression served as a marker for preselection of the models. Nevertheless, other factors may affect response and sensitivity of these tumor models, such as sensitivity to tubulin inhibition, ADC uptake and intracellular processing. In summary, these data support further exploration of the potential of BAY 1129980 in HNSCC, ESCC and bladder cancer in addition to NSCLC. A Phase 1 clinical trial of BAY 1129980 is ongoing (NCT02134197). Citation Format: Joerg Willuda, Carol Pena, Christoph Kneip, Patricia E. Carrigan, Hans-Georg Lerchen, Lars Linden, Bertolt D. Kreft. Response of C4.4A-positive patient-derived xenograft models of ESCC, HNSCC and bladder cancer to BAY1129980, a C4.4A-targeted antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3091. doi:10.1158/1538-7445.AM2017-3091

Abstract CT064: Trial of SBRT and in-situ gene therapy followed by nivolumab in metastatic non-small cell lung carcinoma (ENSIGN)

Abstract The programmed death-1 (PD-1) pathway represents a major tumoral immune resistance mechanism. Although anti-PD-1 blockade with nivolumab has shown great promise in the treatment of metastatic squamous and non-squamous non-small cell lung carcinoma (NSCLC), only a minority of patients derive benefit. Viral vector-based gene therapy such as adenoviral vector-mediated herpes simplex virus tyrosine kinase (ADV/HSV-tk) plus (+) valacyclovir has been shown to induce antitumor immune activity by increasing natural killer cell proliferation and cytotoxicity, cytokine stimulatory activity, and lymphocytic infiltrate. Radiation therapy also augments endogenous antitumor immune responses and often leads to systemic responses at distant sites. This phenomenon, known as the abscopal effect, has been attributed to the induction and enhancement of antitumor immune responses. Based on these findings, we are conducting a Phase II window of opportunity trial of stereotactic body radiation therapy (SBRT) and ADV/HSV-tk in situ gene therapy followed by nivolumab in metastatic squamous or non-squamous NSCLC (NCT02831933). We hypothesize that ADV/HSV-tk + valacyclovir and SBRT will boost endogenous immune-mediated antitumor activity and neoantigen expression, thereby improving the response to nivolumab treatment. The primary endpoint is the objective response rate, and secondary endpoints are duration of response, overall and progression-free survival rates, and antitumor activity. Correlative studies include evaluation of abscopal effect and immune response. ADV/HSV-tk (5 x 1011 viral particles) will be injected intratumorally on Day 0. Valacyclovir (2 g orally 3 times/day) and SBRT (30 Gy; 6 Gy X 5 fractions) will be administered from Day 1 to Day 15 and Day 2 to Day 16, respectively. Nivolumab at a dose of 240 mg will be administered intravenously every 2 weeks starting on Day 17 of the study and continuing until disease progression or unacceptable toxicity. Male or female patients with histologically or cytologically confirmed metastatic squamous or non-squamous NSCLC that has progressed on or after platinum-based chemotherapy or on or after single agent immune checkpoint therapy will be eligible for enrollment. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab. Other eligibility criteria include Eastern Cooperative Oncology Group performance status of 0-1, life expectancy ≥ 6 months, evaluable or measurable disease (RECIST 1.1), target lesion of suitable diameter (at least 1 cm) for SBRT, and non-target lesion of at least 1 cm for abscopal effect evaluation. Twenty-nine patients will be enrolled, and enrollment is expected to begin in February 2017. Citation Format: Eric H. Bernicker, Bin S. Teh, Brian Butler, Jenny C. Chang. Trial of SBRT and in-situ gene therapy followed by nivolumab in metastatic non-small cell lung carcinoma (ENSIGN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT064. doi:10.1158/1538-7445.AM2017-CT064

Nonsmall cell lung carcinoma: diagnostic difficulties in small biopsies and cytological specimens: Number 2 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza.

The pathological and molecular classification of lung cancer has become substantially more complex over the past decade. For diagnostic purposes on small samples, additional stains are frequently required to distinguish between squamous cell carcinoma and adenocarcinoma. Subsequently, for advanced nonsquamous cell nonsmall cell lung carcinoma (NSCLC) patients, predictive analyses on epidermal growth factor receptor, anaplastic lymphoma kinase and ROS1 are required. In NSCLCs negative for these biomarkers, programmed death ligand-1 immunohistochemistry is performed. Small samples (biopsy and cytology) require "tissue" management, which is best achieved by the interaction of all physicians involved.

Correlation between mutation of p53 gene 2-4 exons from peripheral blood and HPV16 positive cervical cancer susceptibility and clinical significance

Objective: To detect mutations of p53 gene 2-4 exons from peripheral blood and to explore their relevance in HPV16-positive cervical cancer susceptibility and clinical significance. Methods: Collected firstly cases from the Third Affiliated Hospital of Kunming Medical University from October 2012 to April 2014, included 167 cases HPV16-postive cervical cancer and 160 cases HPV-negative healthy women. Genomic DNA from the host peripheral venous blood was taken, mutations of p53 gene 2-4 exons were analyzed with software DNAstar after PCR and bidirectional sequencing. Meanwhile, mutations of p53 gene 2-4 exons among different clinicopathological characteristics in HPV16-postive cervical cancer were distinguished. Results: (1) Three mutations and an 16-bp insertion/deletion sequences were found in p53 gene exons 2-4, included C/G mutation of single nucleotide polymorphism (SNP) 11827 in intron2, A/C mutation of SNP11992 in intron3, C/G mutation in codon 72 (rs1042522) of exon4 and 16-bp (acctggagggctgggg) repeat insertion or deletion in intron3 (rs17878362), while deletion recorded as A1, insertion recorded as A2. No significant differences were found in each point allele and genotype frequency (P>0.05) . (2) Stratified analysis for cervical cancer group resulted with some differences. Compared group of non-squamous carcinoma with squamous carcinoma group, there were obviously decreased in allete A2 [11.8% (4/34) vs 3.5% (10/284) ; χ(2)=4.90, P=0.027], genotype A1A2 [4/17 vs 7.0% (10/142) ; χ(2)=5.14, P=0.023], and haplotype C-A2 [11.8% (4/34) vs 3.5% (10/284) ; χ(2)=4.91, P=0.027]. Compared with poorly differentiated group, allele C of SNP11827 and rs1042522 were obviously decreased in medium high differentiation group [50.8% (61/120) vs 38.8% (62/160) ; χ(2)=4.07, P=0.044], while haplotype G-A1 were apparently higher [49.2% (59/120) vs 61.2% (98/160) ; χ(2)=4.07, P=0.044], genotype GG of SNP11827 and rs1042522 were obviously decreased in superficial myometrial invasion depth group than that in deep myometrial invasion depth group [46.3% (25/54) vs 21.1% (8/38) ; χ(2)=7.06, P=0.029]. No significant differences were found between stage Ⅰ and Ⅱ, pelvic lymph node metastasis or not (all P>0.05) . Conclusions: No obvious correlation is found between polymorphisms in exons 2-4 of p53 gene and susceptibility of HPV16-postive cervical cancer. But the patient with allete C and A2, genotype GG and A1A2, haplotype C-A2 and G-A1 may be increase risk of poorly differentiation, deep muscular invasion and bad pathological type. Analysis of p53 gene polymorphism may be provide a basis for the prognosis evaluation and individualized treatment of cervical cancer.

Phase II study of efficacy of bevacizumab plus chemotherapy in management of malignant pleural effusion (MPE) in non-squamous non-small cell lung cancer (NSCLC) patients with MPE unsuccessfully controlled by tube drainage or pleurodesis (North East Japan Study Group Trial NEJ-013B-2).

e21660 Background: Prospective and retrospective studies on intrapleural therapy of malignant pleural effusion (MPE) have reported that the success rate for controlling pleural effusion was 50–70% at 2.5 months, and that the median post-pleurodesis survival time was 6-9 months. When pleurodesis is unsuccessful, and the lung is not fully expanded after drainage, the patients cannot receive effective chemotherapy. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of MPE. Here, a multicenter phase II trial was conducted to evaluate bevacizumab therapy in non-squamous non-small cell lung carcinoma patients with unsuccessful management of MPE. Methods: Non-squamous NSCLC patients with MPE who had received unsuccessful tube drainage or pleurodesis received chemotherapy with bevacizumab (15 mg/kg) every 3 weeks. The primary endpoint was Pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE for 8 weeks. The secondary endpoint was pleural Progression-free survival (PPFS), defined as PFS without reaccumulation of MPE. Results: Fifteen of 20 patients entered received a median of 4 cycles of carboplatin plus paclitaxel or pemetrexed including maintenance therapy with bevacizumab. The PECR was 80% of treated patients (95% CI: 78-82%). PPFS was 16.6 months (95% CI: 11.46-21.80 months). The response rate (RR) and disease control rate (DCR) were 45% (95% CI: 39.6-50.4%), and 80% (95% CI: 78.0-82.0 %), respectively, and the median PFS and overall survival (OS) were 9.8 months (95% CI: 4.38-15.28 months) and 19.6 months (95% CI: 4.38-15.28 months), respectively. Toxicities of grade ≥3 included neutropenia (50.0%), thrombocytopenia (10.0%), proteinuria (10.0%), hypertension (2.0%), pulmonary embolism (5%). Conclusions: The combination of bevacizumab with chemotherapy demonstrated efficacy with acceptable toxicities in controlling MPE in patients with non-squamous NSCLC whose MPE was unsuccessfully controlled by tube drainage or pleurodesis.

Implementation of a multidisciplinary quality improvement initiative to improve molecular testing rates in advanced non-squamous non-small cell lung cancer.

e18181 Background: EGFR mutations and ALK rearrangements are key therapeutic targets in nonsquamous nonsmall cell lung carcinoma (nsNSCLC). Treatment with targeted therapy has been shown to improve progression-free survival and overall survival in many cases. Current guidelines recommend testing all advanced (Stage IIIB and IV) nsNSCLC patients for these genetic aberrations. Our previous work revealed that we were not evaluating a large percentage of eligible patients. In order to improve testing rates, we conducted a series of multidisciplinary meetings aimed at direct physician education and process enhancement. Methods: Utilizing the Association of Community Cancer Centers (ACCC) molecular testing framework in conjunction with support from Pfizer, we launched a lean six sigma initiative aimed at improving our molecular profiling rates. A series of multidisciplinary meetings were conducted addressing action items outlined by the ACCC. A total of 158 advanced nsNSCLC patients were identified from our tumor registry during or shortly after the start of this initiative (2014-2015). Testing rates for EGFR and ALK were determined by individual chart review and compared to our previously published testing rates (2011-2013). Results: We found 77.9% (123/158) and 60.8% (96/158) of patients were tested for EGFR mutations and ALK rearrangements, respectively. We utilized a chi-square test of homogeneity to determine whether there was an increased EGFR and ALK testing rate post-intervention . Our EGFR testing rate increased 80.3%, from 43.2% (2011-2013) to 77.9% (2014-2015), p < 0.00001, and our ALK testing rate increased 155.5%, from 23.8% (2011-2013) to 60.8% (2014-2015), p < 0.00001. Conclusions: Multidisciplinary educational and process enhancement meetings improve molecular testing rates in nsNSCLC.

Androgen Receptor Expression in Primary Nonsquamous Cell Rare-Variant Carcinomas of the Head and Neck.

ObjectiveAndrogen receptor (AR) is a diagnostic immunohistochemical marker for salivary gland duct carcinoma (SDC), but other nonsquamous cell head and neck carcinomas (NSCCs) may also express it. The aim of this preliminary study was to investigate the immunohistochemical expression of AR in rare head and neck NSCCs.Study DesignRetrospective analysis of histologic records.SettingA large community hospital.Subjects and MethodsTwenty-seven patients with NSCC were selected (21 men, 6 women; average age, 69 years). Exclusion criteria were histologically confirmed primary and metastatic head and neck squamous cell carcinomas and thyroid carcinomas. AR immunohistochemistry was done on formalin-fixed, paraffin-embedded tissue blocks.ResultsVariable AR expression was found in 5 of 27 (25%) cases of NSCC. All 7 patients with SDC showed intense and extensive positive immunoreactivity. Of 27 NSCC tumors, 15 (56%) had negative staining.ConclusionIn the head and neck, expression of AR is not limited to SDCs; other NSCCs also express it. When surgery or radiotherapy is not appropriate for recurrent or metastatic head and neck NSCC, palliative chemotherapy offers poor results. Antiandrogen therapy is well tolerated and is much less toxic than chemotherapy. Since androgen deprivation therapy has been used against SDCs, this therapy may theoretically be used in a small subset of head and neck NSCCs.

Non–Small-cell Lung Cancer Patients With Adenocarcinoma Morphology Have a Better Outcome Compared With Patients Diagnosed With Non–Small-cell Lung Cancer Favor Adenocarcinoma

BackgroundNon–small-cell lung cancer (NSCLC) includes 2 major histologic subtypes: squamous cell carcinoma and non-squamous carcinoma, mainly adenocarcinoma, a distinction that carries significant clinical and therapeutic implications. NSCLC is diagnosed as adenocarcinoma or as squamous cell carcinoma on the basis of histologic parameters. However, when morphology is inconclusive, tumors with immunohistochemistry (IHC) findings characteristic of adenocarcinoma are referred to as “NSCLC favor adenocarcinoma” (NFA). Our aim was to evaluate whether pulmonary adenocarcinoma diagnosis on the basis of morphology had a similar prognosis compared with NFA. Patients and MethodsPatients with advanced NSCLC non-squamous carcinoma who were treated with a platinum-pemetrexed doublet as first-line combination chemotherapy were identified. Demographic, clinical, laboratory, and pathological data including the method of pathological diagnosis (morphology or IHC) was extracted from the clinical charts. The correlation between the various parameters and overall survival was evaluated. ResultsLack of adenocarcinoma morphology, male sex, smoking history, and negative thyroid transcription factor 1 IHC were associated with worse prognosis and shorter overall survival in multivariate analysis. High white blood cell count, absolute neutrophil count, neutrophil to lymphocyte ratio, and low albumin levels were associated with shorter overall survival only in univariate analysis. ConclusionPulmonary adenocarcinoma has a better prognosis than NFA, regarding advanced NSCLC treated with platinum-pemetrexed combination chemotherapy. This distinction should be a stratification factor in clinical trials and a prognostic factor to consider in analysis of previous trials.

P3.02c-084 Predictive and Prognostic Clinical and Pathological Factors of Nivolumab Efficacy in Non-Small-Cell Lung Cancer (NSCLC) Patients: Topic: IT Biomarkers

Immunotherapy with anti-PD1 and anti-PDL1 monoclonal antibodies significantly increases overall response rate (ORR) and overall survival (OS) of patients with advanced NSCLC in comparison with second line conventional chemotherapy. Prognostic and predictive factors able to distinguish those patients with a higher benefit from immunotherapy are warranted. Our work retrospectively analyses several clinical, pathological and analytical variables with an eventual potential prognostic and predictive value in daily patients with advanced NSCLC receiving Nivolumab. A retrospective review of clinical charts of patients with advanced NSCLC from fourteen centres of the GIDO group receiving Nivolumab between May-2015 and May-2016 was performed. Age, sex, stage, Performance Status (PS), location of metastases, presence of tumor-related symptoms and comorbidities, number of organs with metastasis, previous chemotherapy, antiangiogenic and radiotherapy treatments, and analytical data from standard blood count and biochemistry were collected and statistically analyzed. A total of 175 patients fulfilled inclusion criteria. Median age was 61.5 years. One hundred and twenty-eight male (73.1%), 136 ECOG-PS 0-1 (77.7%), 150 stage IV (86,7%) and 135 had non-squamous carcinoma histology (77.1%). Sixty-five received Nivolumab in second line (37.1%), 66 as third line (37.1%) and 44 as forth or further line of treatment (25.1%). Seventeen patients (9.7%) received antiangiogenic drug in previous line of treatment, and 30 were treated with radiotherapy within 30 days before Nivolumab. Thirty-eight patients had brain metastasis (22%), 39 liver metastasis (22.3%) and 126 had more than one metastatic location (72%). 140 patients were evaluable for response, the ORR was 15.7%, median Progression Free Survival was 2.8 months, and median OS 5.81 months. Stage III (OR 3.57) and time since the beginning of previous line of treatment longer than 6 months (OR 2.52) were associated in multivariable analysis with higher probability of response to Nivolumab. PS 2 vs 0-1 (HR 1.83), time since the beginning of previous line of treatment <6 vs >6 months (HR 1,70) and more than one metastatic location vs one location (HR 1.79) were independently associated with shorter overall OS in multivariable analysis. Poor Performance Status, short period of time since the beginning of previous treatment and more than one metastatic location are the clinical-pathological features associated with poorer prognostic in patients with advanced NSCLC treated with Nivolumab. Limitations of the study are the small numbers and the retrospective nature.

466 - Phase I study of ganetespib and ziv-aflibercept in patients with advanced gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas

466 - Phase I study of ganetespib and ziv-aflibercept in patients with advanced gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas

Could molecular pathology testing in lung cancer be more cost-effective?

EGFR and ALK analysis is routinely undertaken prior to targeted treatment of non-squamous non-small cell lung carcinoma (NSCLC). Increasingly, limited resources require molecular pathology services to be cost-effective without detriment to patient care. Data from an audit of molecular pathology testing in the South East Scotland Cancer Network (SCAN) network have been used to explore different testing strategies with the aim of reducing costs; including investigation of thyroid transcription factor 1 (TTF1) expression as a negative predictor for EGFR mutations. TTF1 immunohistochemistry had a high negative predictive value for EGFR mutations (99%). Reflex testing all non-squamous NSCLC, as expected, had the highest costs, whereas limiting testing to those who might be considered for treatment would lead to a cost reduction of only 7.5%; however, a serial testing model could save 32.7%. Testing only patients being considered for EGFR and ALK inhibitors represented small savings; more significant savings would be achievable if testing algorithms used known associations between clinical biomarkers.

A phase II study of bevacizumab with carboplatin-pemetrexed in non-squamous non-small cell lung carcinoma patients with malignant pleural effusions: North East Japan Study Group Trial NEJ013A

BackgroundVascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of malignant pleural effusion (MPE). Here, a multicenter phase II trial to evaluate bevacizumab in non-squamous non-small cell lung carcinoma patients with MPE was conducted. MethodsPatients having MPE with no prior treatment and performance status of 0–2 received carboplatin (area under the curve: AUC 6; up to 6 cycles) and pemetrexed (500mg/m2) with bevacizumab (15mg/kg) every 3 weeks. The primary endpoint was the control rate of MPE without pleurodesis at 8 weeks after treatment. VEGF levels in plasma and MPE were measured by enzyme immunoassay. ResultsOf 30 patients entered (median 66 years; 24 males; adenocarcinoma; 4 epidermal growth factor receptor: EGFR mutations), 28 patients (2 withdrawn patients) were given a median of 4 cycles of carboplatin, and 68% of the patients received maintenance pemetrexed with bevacizumab (median 8 cycles). At eight weeks, MPE was controlled without pleurodesis in 93% of treated patients (95% confidence interval: 77–99%). At the median follow-up time of 12.8 months, 78.6% of the cases required no pleurodesis. Response rate was 46%, and median progression-free survival (PFS) and overall survival (OS) were 8.2 months and 18.6 months, respectively. Toxicities of grade ≥3 included neutropenia (28.6%), thrombocytopenia (28.6%), proteinuria (3.6%), and hypertension (3.6%). Assessment of VEGF levels before treatment indicated that patients with low VEGF (<1000pg/ml) in MPE frequently needed pleurodesis (p=0.011), and that high VEGF (≥100pg/ml) in plasma was indicative of poor prognosis in the context of PFS (p=0.012). ConclusionThe combination of bevacizumab with carboplatin and pemetrexed demonstrated efficacy with acceptable toxicities in patients with MPE.

Phase 3 study of platinum-based chemotherapy with or without pembrolizumab for first-line metastatic, nonsquamous non-small cell lung carcinoma (NSCLC): KEYNOTE-189.

TPS9104Background: Platinum-based chemotherapy is the standard of care for treatment-naive NSCLC patients without an activating EGFR mutation or ALK gene rearrangement. Preliminary data from the phase 1/2 KEYNOTE-021 (NCT02039674) study suggest manageable toxicity and encouraging efficacy of platinum-doublet chemotherapy plus pembrolizumab, an anti–PD-1 monoclonal antibody, in treatment-naive NSCLC. KEYNOTE-189 (NCT02578680) is a randomized, double-blind, phase 3 study to compare the efficacy and safety of platinum-doublet chemotherapy with/without pembrolizumab as first-line treatment in nonsquamous NSCLC. Methods: Patients ≥ 18 years with advanced nonsquamous NSCLC in whom EGFR- or ALK-directed therapy is not indicated, ECOG PS 0-1, and no prior systemic chemotherapy are eligible. Approximately 570 patients will be randomly assigned (2:1) to pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5 Q3W for 4 cycles followed by pembrolizumab 200 mg plus pemetrexed 500 mg/...

Sinonasal Squamous Cell Carcinoma: A Review with Emphasis on Emerging Histologic Subtypes and the Role of Human Papillomavirus.

The sinonasal tract is one of the least frequent sites for squamous cell carcinoma in the head and neck. However, it is still a complex tumor type for pathologists because there are numerous histologic variants with unusual morphologic features, several non-squamous carcinomas in the differential diagnosis that can have similar morphology and even squamous differentiation, and because of the increasing recognition of human papillomavirus (HPV) in a subset of the tumors. In addition, the unique and complex anatomy of the sinonasal tract can make proper staging and management of patients' tumors quite challenging. This article reviews sinonasal tract squamous cell carcinoma in depth and provides the latest data on Schneiderian papillomas and HPV in their pathogenesis.

Traitement de 1re ligne des cancers bronchopulmonaires non à petites cellules de stade IV en l'absence d'addiction oncogénique

Despite the identification of genetic alteration responsible for tumor genesis in an increasing part of stage IV NSCLC patients, cytotoxic chemotherapy remains the cornerstone of treatment for the vast majority of patients for which there is no targetable oncogenic addiction. First-line chemotherapy remains based on the combination of cisplatin or carboplatin with a third-generation cytotoxic agent for patients with a good performance status (0 or 1). Besides the improvement of supportive care for chemotherapy, several advances have led to improve overall survival of stage IV patients as the consideration of histology for treatment selection, the use of pemetrexed for non-squamous carcinoma, maintenance strategies in first-line, or the addition to chemotherapy of an anti-angiogenic agent in non-squamous carcinoma or an anti-EGFR monoclonal antibody in squamous cell carcinoma. New therapeutic options as immunotherapy will likely lead to a later use of chemotherapy for stage IV NSCLC patients in the next future.

EGFR mutation status in Middle Eastern patients with non-squamous non-small cell lung carcinoma: A single institution experience

BackgroundEpidermal growth factor receptor (EGFR) represents an important molecular target in the treatment of lung adenocarcinomas; many anti-EGFR therapies are approved as first line and second-line treatment in patients having metastatic lung adenocarcinomas. The occurrence of this mutation varies in terms of race; it is around 10% in Caucasians and can reach 30% in Asians. Its prevalence in our Middle Eastern region is not well known. MethodsPatients diagnosed with non-squamous non-small cell lung carcinomas between March 2013 and March 2015 were included. This study was conducted at Hôtel-Dieu de France University Hospital, a tertiary medical center in Lebanon. EFGR mutations were analyzed using real time PCR technique on the Rotor-Gene Q using Scorpions and ARMS technologies. The following data was collected: the patients’ characteristics (age, gender, smoking status, stage), the samples’ characteristics (histology subtype, TTF-1 and Napsin A immunostainings, the site and the adequacy and the type of the sample), and the mutational EGFR status (presence and type of mutation). These variables were analyzed using SPSS 20. Results201 patients were included. The mean age was 65.2 years [31–87]; 40.2% were females. 78.1% of the included patients were smokers or ex-smokers. 12.9% of patients had a localized disease, 17.4% a locally advanced disease and 69.7% a metastatic disease. Adenocarcinoma was the main histologic subtype found in 90.5% of patients, followed by large cell carcinoma (3.5%), adenosquamous carcinoma (3.0%) and non-small cell carcinoma not otherwise specified (3.0%). 11.9% of patients had an EGFR mutation: 48% of them presented a deletion on exon 19, 40.0% a L858R mutation on exon 21, 4.0% a G719X mutation in exon 18, 4.0% an insertion in exon 20, and 4% a T790M mutation in exon 20. The presence of an EGFR mutation was significantly associated with the female gender (two-third) (p<0.05) and the non-smoking status (two-third) (p<0.05). ConclusionsThe prevalence of EGFR mutation (11.9%) detected in our Lebanese population is similar to that observed in the Caucasian population. This mutation is also significantly more frequent in females and non-smokers.

Reliability and validity of the Cancer Therapy Satisfaction Questionnaire in lung cancer.

PurposeTo test the reliability and validity of the Cancer Treatment Satisfaction Questionnaire (CTSQ), to assess its relation with quality of life (QoL), and to assess the interpretability of the domain scores in lung cancer patients receiving intravenous chemotherapy.MethodsPatients with stage IIIB and IV non-squamous non-small cell lung carcinoma treated with pemetrexed were enrolled in our study. They completed the 16-item CTSQ and two other (health-related) QoL questionnaires. Information about sociodemographic characteristics, cancer stage, and the experience of adverse events was collected. Internal consistency, construct validity, and clinical interpretability were calculated.ResultsFifty-five patients completed the CTSQ. Correlations of the CTSQ items with its domain were all above 0.40. A high correlation between item 8 and the expectations of therapy and satisfaction with therapy domain was observed (0.50 and 0.48, respectively). The CTSQ domains demonstrated good internal consistency and low to moderate correlations of the CTSQ with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and World Health Organization Quality of Life-BREF. No significant differences in mean domain scores were observed in relation to the number and severity of different adverse events and chemotherapy-related adverse events.ConclusionsThe Dutch version of the CTSQ was found to be a reliable and valid instrument to assess satisfaction and expectations of treatment in lung cancer patients receiving intravenous chemotherapy. Furthermore, the CTSQ proved to be of additional informative value as not all of its domains correlated with the various domains of the existing HRQoL instruments.